Synthesis of vicinal difluoro aromatics and intermediates thereof

ABSTRACT

A method of preparing vicinal difluoro aromatic compounds in high yield from hydroxy aromatic compounds and a method of preparing intermediates thereof. The hydroxy aromatic compound can be a mono-, bi- or tricyclic aromatic in which the rings are separate or fused. One or more of the rings can contain heteroatoms, such as oxygen, nitrogen, or sulfur, and can contain one or more substitutions, in addition to the hydroxy substitution.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of Application Ser. No. 09/985,786, filedon Nov. 6, 2001, now U.S. Pat. No. 6,455,744, which is acontinuation-in-part of U.S. application Ser. No. 09/767,636, filed onJan. 23, 2001, abandoned.

BACKGROUND OF THE INVENTION

Aromatic compounds, especially naphthalene derivatives, bearing fluorineatoms on adjacent carbons (i.e., vicinal) have been found to be usefulas liquid crystal materials. They are typically made by a multi-stepprocess, starting from the aromatic amine via a fluoro-dediazoniationprocess (N. Yoneda and T. Fukuhara, Tetrahedron, vol. 52, No. 1 (1996),pages 23-36).

No simple methods are known for producing vicinal difluoro aromaticcompounds. Methods for defluorinating highly fluorinated compounds areknown; but, none of the methods have been shown to produce vicinaldifluoro compounds in high yield. For example:

C. Hu, et al., Journal of Fluorine Chemistry, Vol. 48 (1990), pages29-35, disclosed a method of synthesizing perfluoroaromatics, such astetradecafluorobicyclo[4.4.0]dec-1(2),6(7)-diene and perfluorotetralin,by defluorination of hexadecafluorobicyclo[4.4.0]dec-1(6)-ene in anaprotic solvent using activated zinc powder as a catalyst. The extent ofdefluorination depended on the polarity of the aprotic solvent used.

J. Burdon and I. W. Parsons, Journal of Fluorine Chemistry, Vol. 13(1979), pages 159-162, disclose the formation of 2,5-difluorothiophen bypyrolysis of 2,2,5,5-tetrafluoro-3-thiolen over sodium fluoride.

Sergey S. Laev and Vitalii D Shteingarts, Journal of Fluorine Chemistry,Vol. 96 (1999) pages 175-185, disclose the reductive dehalogenation ofpolyfluoroarenes by zinc in aqueous ammonia. In the reaction, hydrogenatoms replace fluorine atoms in the polyfluoroarenes.

JP 2001-10995A (Ogawa, et al.) describes a four-step process forsynthesis of vicinal difluoro aromatic compounds involving fluorinationof a hydroxy aromatic compound to form a tetrafluoro intermediate in twosteps followed by hydrogenation and defluorination under basicconditions. It also discloses reduction of a difluoroketone intermediatewith aluminum isopropoxide and then base-catalyzed dehydrohalogenationto form a difluoro aromatic compound. A third method involves reactionof the difluoroketone with lithium aluminum hydride to form afluoroepoxide, addition of HF, and elimination of water to give avicinal difluoro aromatic compound. The best overall yield shown is<50%.

There remains a need for an effective and simple method for preparingvicinal difluoro aromatic compounds in high yield.

BRIEF SUMMARY OF THE INVENTION

This invention is directed to a method of preparing vicinal difluoroaromatic compounds in high yield from hydroxy aromatic compounds and topreparing intermediates thereof. The hydroxy aromatic compound can be amono-, bi- or tricyclic aromatic in which the rings are separate orfused. One or more of the rings can contain heteroatoms, such as oxygen,nitrogen, or sulfur, and can contain substitutions, in addition to thehydroxy substitution. Substitutions on one or more of the rings caninclude a halogen atom, a C1 to C20 alkyl, a C5-C10 cycloalkyl, a C6 toC12 aryl, an amino, a nitro, a C1 to C10 alkyl ether or thioether, a C1to C10 alkyl ester, a CF₃, a R′SO₂O,

where R′ is CF₃, a C1 to C20 alkyl, a substituted or unsubstituted C5 toC10 cycloalkyl, or a substituted or unsubstituted C6 to C12 aryl, inwhich the substitution on the cycloalkyl or aryl can be a C1 to C20alkyl or a C5 to C8 cycloalkyl; R″ is a C1-C10 saturated or unsaturatedalkyl; x is an integer from 0 to 10, and y is an integer from 0 to 10.

The process can be described by the following reaction steps:

where R is a hydrogen atom, a halogen atom (Cl, Br, I, F), R′SO₂O, CF₃,a fused aryl, a C1-C20 alkyl, amino, nitro, a C1 to C10 ether orthioether, a C1 to C10 ester, a heteroaryl, wherein the heteroatom canbe O, N, S,

or R forms an aryl. R′ is CF₃, a C1 to C20 alkyl, a substituted orunsubstituted C5 to C10 cycloalkyl, or a substituted or unsubstituted C6to C12 aryl, wherein the substitution on the cycloalkyl or aryl can be aC1 to C20 alkyl or a C5 to C8 cycloalkyl; R″ is a C1-C10 saturated orunsaturated alkyl; x is an integer from 0 to 10, and y is an integerfrom 0 to 10. The preferred R group is trans-4-propylcyclohexyl.

The yields obtained from reactions (1) and (2) are highly dependent onthe solvents employed for these steps. Polar aprotic solvents aredesirable for the electrophilic fluorination in step (1) anddimethylformamide (DMF) is particularly preferred because itunexpectedly resulted in yields of greater than 95% difluoro ketoneproduct. Reaction step (2) can be conducted in various solventsincluding aliphatic and aromatic hydrocarbons, halocarbons, ethers,etc.; however, toluene unexpectedly gives much higher yields of thetetrafluoro product compared to other organic solvents. Step (3)involves reacting the tetrafluoro compound with a reducing agent, suchas metallic zinc, copper, magnesium, or a mixture thereof, to form thevicinal difluoro aromatic compound in high yields (e.g., 90% or more).This reaction is preferably carried out in buffered aqueous ammonia inthe presence of an organic solvent such as tetrahydrofuran (THF), methyltert-butyl ether, acetonitrile, ethanol, or DMF. Since the tetrafluorocompound reacts under basic conditions to form a trifluoronaphthaleneby-product, the pH of the aqueous ammonia is buffered to <14 by additionof an ammonium salt, particularly NH₄Cl. Under these conditions, theselectivity to the desired vicinal difluoronaphthalene product issignificantly increased.

This method of preparing vicinal difluoro aromatic compounds has thefollowing advantages over known methods:

the difluoro ketone and tetrafluoro intermediates do not need to bepurified prior to subsequent reaction,

the product is produced in high selectivity,

the overall yield is 70% or more, and

the product easily can be separated and purified by known methods.

DETAILED DESCRIPTION OF THE INVENTION

In the method of this invention, vicinal difluoro aromatic compounds canbe prepared in three steps from hydroxy aromatic compounds byelectrophilic fluorination using a fluorination reagent such asSelectfluor® reagent(1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanebis-tetrafluoroborate) to form a difluoroketone intermediate. Thedifluoro ketone undergoes nucleophilic fluorination by reaction with adeoxofluorinating reagent such as Deoxo-Fluor® reagent(bis(2-methoxyethyl)-aminosulfur trifluoride) to give a tetrafluorointermediate species. The tetrafluoro intermediate is defluorinated by ametallic reducing agent in the presence of ammonium hydroxide,preferably buffered ammonium hydroxide, to provide the desired vicinaldifluoro aromatic compound in high yield. An example of the reactionchemistry is described above in the Brief Summary of the Invention.

In the first step, a hydroxy aromatic compound (e.g., β-naphthol orsubstituted naphthol) is reacted with an electrophilic fluorinatingagent such as Selectfluor reagent, to generate a difluoroketoneintermediate. This reaction can be conducted in various solventsincluding nitrites such as acetonitrile (CH₃CN), formamides such asdimethylformamide (DMF), CH₃NO₂, carboxylic acids such as acetic acid,water, and an alcohol such as methanol, ethanol, and propanol.

The reaction can be carried out at temperatures ranging from 0° C. tothe boiling point of the solvent.

The fluorinating agent can be added to a solution or suspension of thehydroxy aromatic compound in one or more portions, or dropwise as asolution. Alternatively, the hydroxy aromatic compound solution orsuspension can be added to a solution or suspension of fluorinatingagent.

In the second step, the carbonyl oxygen of the difluoroketone isreplaced by two fluorine atoms using a deoxofluorinating agent such asDeoxo-Fluor reagent. The reaction is carried out by reacting thedifluoroketone with the deoxofluorinating agent in an organic solvent inan anhydrous atmosphere. Solvents include alkanes such as hexane,heptane, etc.; aromatic hydrocarbons such as toluene, xylenes, etc.;haloalkanes such as methylene chloride, chloroform, etc.; ethers, suchas diethyl ether, THF, etc.; and any other solvent that will not reactwith the fluorinating reagent.

The reaction temperature can range from 0° C. to 90° C. In carrying outthe reaction, the difluoroketone can be mixed with the entire charge ofthe fluorinating reagent or the reagent can be added dropwise to asolution of the difluoroketone. Lewis acid catalysts such as borontrifluoride etherate (BF₃.Et₂O) or HF can be used to accelerate thereaction. The product obtained is usually a mixture of the desired1,1,2,2-tetrafluoro compound and the corresponding 1,1,2,4-tetrafluoroisomer. We have found that both the yield and the isomer ratio arehighly dependent on the solvent used. Toluene is unexpectedly superiorto other organic solvents in producing a high yield of the desiredisomer. For example, when THF was used as solvent at 60° C., a 65% yieldof1,1,2,2-tetrafluoro-6-trans-4-propylcyclohexyl)-1,2-dihydronaphthalenewas obtained (1,1,2,2-tetrafluoro/1,1,2,4-tetrafluoro=51/49), while whentoluene was used as solvent at the same temperature, an 85% yield wasobtained (1,1,2,2-tetrafluoro/1,1,2,4-tetrafluoro=90/10) under the samereaction conditions.

In the third step of the process, the mixture of tetrafluoro isomers isreductively defluorinated using a reducing agent in an aqueous ammoniasolution, preferably a buffered aqueous ammonia medium. Both tetrafluoroisomers react to form the same vicinal difluoro aromatic product.

The reducing agent in this method can be metallic zinc or other knownreducing agents, such as copper, magnesium, or mixtures thereof. Themetals typically are used in powder form, but other forms should also beeffective. Reducing agents that do not react rapidly with water arepreferred. At least one molar equivalent of the reducing agent, based onthe amount of starting compound, is needed.

The process of reductive defluorination is preferably carried out inbuffered aqueous ammonia with an organic co-solvent, such as THF. Theorganic co-solvent can be used to make a solution of the tetrafluoroaromatic compound. Other co-solvents that can be used include etherssuch as methyl tert-butyl ether; nitrites such as acetonitrile; alcoholssuch as ethanol; and amides such as DMF. The aqueous ammonia is bufferedto a pH <14 and preferably <11 with an ammonium salt; preferablyammonium chloride. Maintaining a pH below 14, minimizes the productionof unwanted by-products. For example, when the reaction medium is toobasic (i.e., a pH of 14), 1,1,2,2-tetrafluoro dihydronaphthalene isconverted to a 1,2,4-trifluoronaphthalene compound as shown in thereaction below:

The rate of this reaction has been found to be pH-dependent, andconsequently the selectivity to this impurity is significantly reducedas the pH is reduced below 14, especially below 11.

Typically 3.2 ml of ammonium hydroxide and 1.6 ml of organic solvent permmol of starting compound are appropriate for the reaction.

The reaction can be carried out at temperatures ranging from 0° C. tothe boiling point of the solvent; preferably 25 to 45° C.

The reaction can be run in air or more preferably under an inert gas,such as nitrogen.

The reaction can be monitored by methods known in the art to determinecompletion. For example GC or GC/MS (gas chromatography/massspectrometry) can be used to determine when the reaction is complete.Reaction times typically range from 2-48 hours.

The vicinal difluoro aromatic product can be isolated from the reactionmixture by methods known in the art. For example, the product can beisolated by filtering the reducing metal, extracting the aqueous layerinto an immiscible organic solvent, evaporating the solvent, andpurifying the product using chromatography, distillation, and/orrecrystallization.

The invention will be further clarified by a consideration of thefollowing examples, which are intended to be purely exemplary of theinvention.

EXAMPLE 1

Synthesis of1,1-Difluoro-(trans-4-Propylcyclohexyl)-1H-Naphthalene-2-one Using DMFSolvent

A suspension of 6-(trans-4-propylcyclohexyl)naphthalene-2-ol (30 g,111.9 mmol) in DMF (180 ml) was treated with Selectfluor reagent (79.9g, 224.4 mmol) in 5 equal portions at 15 minute intervals. The mixturewas stirred for a further 4 hours (h) at room temperature (RT). Oncompletion, the reaction mixture was washed with water (2×100 ml) andNaHCO₃ (100 ml), dried (MgSO₄), filtered, and evaporated in vacuo. Afterpurification by column chromatography on silica gel (ethylacetate/hexanes 1/9), the product (33.6 g, 98%) was obtained. Use of DMFunexpectedly resulted in a substantially higher yield of productcompared to use of CH₃CN in Example 2.

EXAMPLE 2

Synthesis of1,1-Difluoro-(trans-4-Propylcyclohexyl)-1H-Naphthalene-2-one UsingAcetonitrile Solvent

A suspension of 6-(trans-4-propylcyclohexyl)naphthalene-2-ol (30 g,111.9 mmol) in CH₃CN (225 ml) was treated with Selectfluor reagent (79.9g, 224.4 mmol) in 5 equal portions at 15 min intervals. The mixture wasstirred for a further 4 h at RT. On completion, the reaction mixture wasextracted with 100 ml of toluene, washed with water (2×100 ml) andsaturated NaHCO₃ (100 ml), dried (MgSO₄), filtered, and evaporated invacuo. The residue was chromatographed on silica gel (ethylacetate/hexanes 1/9) to obtain the product (25.37 g, 74%). MS: m/e=304(M⁺)

EXAMPLE 3

Synthesis of1,1,2,2-Tetrafluoro-6-(trans-4-Propylcyclohexyl)-1,2-DihydronaphthaleneUsing Toluene Solvent

A solution of1,1-difluoro-(trans-4-propylcyclohexyl)-1H-naphthalene-2-one (2.0 g, 6.6mmol) in toluene (5 ml) was heated to 60° C. in a teflon tube under N₂.To this solution was added the Deoxo-Fluor reagent dropwise (2.48 g, 2.1ml, 11.22 mmol). The mixture was heated for a further 5 h. On cooling to0° C., the solution was treated with 0.5 ml of methanol (MeOH) andsaturated NaHCO₃. After CO₂ evolution ceased the solution was dilutedwith 20 ml toluene and the organic layer was separated, dried (MgSO₄),filtered, and evaporated in vacuo. The residue was purified bychromatography on silica gel (hexanes as solvent) to obtain the pureproduct (1.82 g, 85% yield as a 90/10 mixture of the title product andthe 1,1,2,4-tetrafluoro isomer). MS: m/e 326 (M⁺).

EXAMPLE 4

Synthesis of1,1,2,2-Tetrafluoro-6-(trans-4-Propylcyclohexyl)-1,2-DihydronaphthaleneUsing THF Solvent

A solution of1,1-difluoro-(trans-4-propylcyclohexyl)-1H-naphthalene-2-one (2.0 g, 6.6mmol) and Deoxo-Fluor reagent (2.48 g, 2.1 ml, 11.22 mmol) in THF (4 mL)was heated for 3 h at 60° C. in a teflon tube under N₂. On cooling to 0°C., the solution was treated with MeOH (0.5 ml) and saturated NaHCO₃.After CO₂ evolution ceased, the solution was diluted with 20 ml EtOAcand the organic layer was separated, dried (MgSO₄), filtered, andevaporated in vacuo. The residue was purified by chromatography onsilica gel (hexanes as solvent) to obtain the pure product (1.39 g, 65%yield as a 51/49 mixture of the title product and the1,1,2,4-tetrafluoro isomer). MS: m/e 326 (M⁺).

EXAMPLE 5

Synthesis of1,1-Difluoro-6-(Trans-4-Propylcyclohexyl)-1,2-Dihydronaphthalene-2-One

A solution containing 6-(trans-4-propylcyclohexyl)-2-naphthol, 100.3 g(0.37 mole), in 200 ml of DMF was added dropwise to a slurry ofSelectfluor reagent, 304.5 g (0.86 mole) in 250 ml of DMF while stirringunder N₂. The temperature of the reaction mixture was maintained below30° C. After the addition was completed, the reaction mixture wasstirred at ambient temperature, and sampled periodically for analysis bygas chromatography. When the GC results showed no detectable startingmaterial, the reaction was terminated. Toluene, 450 ml, and water, 375ml, were added. The mixture was stirred and then transferred to aseparatory funnel. The aqueous layer was withdrawn, and the organiclayer was washed with 2×400 ml of water. An orange solid, 106.7 g (94%yield) was recovered after evaporation of the solvent from the organicphase. The product was characterized by GC and NMR analyses. Thisexample shows that purification of the intermediate is not required.

EXAMPLE 6

Synthesis of1,1,2,2-Tetrafluoro-6-(trans-4-Propylcyclohexyl)-1,2-Dihydronaphthalene

1,1-Difluoro-6-(trans-4-propylcyclohexyl)-1,2-dihydronaphthalene-2-one(47.9 g, 0.16 mole) was dissolved in toluene and charged to a Teflonvessel. The reactor was purged with N₂, then sealed and heated to 60° C.When the temperature reached 60° C., Deoxo-Fluor reagent, 49.4 ml (0.27mole), was added via syringe. The reaction mixture was stirred at 60-65°C. until GC analysis showed that the starting material had beenconsumed. The mixture was cooled to 10° C., and quenched by addingmethanol then neutralized by adding 10% KOH. The mixture was transferredto a separatory funnel, and the aqueous layer was withdrawn. The organiclayer was washed with 5% NaHCO₃ solution. The product, 48.5 g, wasisolated as an oil after evaporation of the solvent and was analyzed byGC and NMR.

EXAMPLE 7

Synthesis of 1,2-Difluoro-6-(trans-4-Propylcyclohexyl)Naphthalene

A mixture of1,1,2,2-tetrafluoro-6-(trans-4-propylcyclohexyl)-1,2-dihydronaphthaleneand1,1,2,4-tetrafluoro-6-(trans-4-propylcyclohexyl)-1,2-dihydronaphthalene,10.0 g (30.6 mmol) in THF was stirred with zinc dust (10 g, 153 mmol)and aqueous 30% NH₄OH at ambient temperature. After 27 h, GC analysisshowed that the mixture contained <1% of the starting material. Themixture was filtered, and the zinc was washed with hexanes. The filtratewas transferred to a separatory funnel, the phases were separated, andthe solvent was evaporated from the organic phase. The weight of productrecovered was 8.6 g. GC analysis of the product showed that it contained0.9%1,1,2,2-tetrafluoro-6-(trans-4-propylcyclohexyl)-1,2-dihydronaphthalene,13.4% 1,2,4-trifluoro-6-(trans-4-propylcyclohexyl)naphthalene, and 82%1,2-difluoro-6-(trans-4-propylcyclohexyl)naphthalene. This example showsthat when ammonia is not buffered to reduce the pH, more by-products areformed compared to the reaction in which buffered ammonia is used(Example 8).

EXAMPLE 8

Synthesis of 1,2-Difluoro-6-(trans-4-Propylcyclohexyl)Naphthalene UsingBuffered Ammonia

A mixture of1,1,2,2-tetrafluoro-6-(trans-4-propylcyclohexyl)-1,2-dihydronaphthaleneand1,1,2,4-tetrafluoro-6-(trans-4-propylcyclohexyl)-1,2-dihydronaphthalene,25.6 g (78.4 mmol) in THF was stirred at ambient temperature with zincdust (25.0 g, 382 mmol) and a solution containing ammonium chloridedissolved in aqueous 30% NH₄OH. The reaction was terminated after 48 h.The mixture was filtered, and the zinc was washed with hexanes. Thefiltrate was transferred to a separatory funnel, the phases wereseparated, and the solvent was evaporated from the organic phase. Theweight of product recovered was 21.9 g. GC analysis of the productshowed that it contained 0.2%1,1,2,2-tetrafluoro-6-(trans-4-propylcyclohexyl)-1,2-dihydronaphthalene,2.1% 1,2,4-trifluoro-6-(trans-4-propylcyclohexyl)naphthalene, and 93.1%1,2-difluoro-6-(trans-4-propylcyclohexyl)naphthalene.

EXAMPLE 9

Synthesis of 1,2-Difluoro-6-(trans-4-Propyl-Cyclohexyl)Naphthalene Usinga Cu—Zn Catalyst

1,1,2,2-Tetrafluoro-6-(trans-4-propylcyclohexyl)-1,2-dihydronaphthalene,10.0 g (30.6 mmol) in THF was stirred at ambient temperature with zincdust (10 g, 153 mmol), copper powder (5.0 g, 79 mmol), and a solutioncontaining ammonium chloride dissolved in aqueous 30% NH₄OH. The copperpowder was prepared by reduction of copper sulfate pentahydrate withzinc. After 24 h, the reaction was terminated. The mixture was filtered,and the copper-zinc was washed with hexanes. The filtrate wastransferred to a separatory funnel, the phases were separated, and thesolvent was evaporated from the organic phase. The weight of productrecovered was 8.2 g. GC analysis of the product showed that it contained0.1%1,1,2,2-tetrafluoro-6-(trans-4-propylcyclohexyl)-1,2-dihydronaphthalene,1.7% 1,2,4-trifluoro-6-(trans-4-propylcyclohexyl)-naphthalene, and 94%1,2-difluoro-6-(trans-4-propylcyclohexyl)naphthalene.

EXAMPLE 10

Synthesis of 1,2-Difluoronaphthalene from 2-Hydroxynaphthalene

(a) Formation of 1,1-difluoro-1H-naphthalene-2-one

A suspension of 2-hydroxynaphthalene (5.0 g, 34.72 mmol) in DMF (50 ml)under N₂ was treated with Selectfluor reagent (24.58 g, 69.44 mmol) ineight equal portions at 15 min intervals. The mixture was stirred for afurther 1 h, diluted with 50 ml of ethyl acetate (EtOAc), washed withwater (2×25 ml), dried (MgSO₄), filtered, and evaporated in vacuo.Purification by flash chromatography on silica gel (1:9 ethylacetate/hexanes) furnished the product (6.12 g, 98% yield). MS: m/e 180(M⁺)

(b) Formation of 1,1,2,2-tetrafluoro-1,2-dihydronaphthalene

To a solution of 1,1-difluoro-1H-naphthalene-2-one (6.12 g, 34 mmol) intoluene (5 ml) under N₂ in a teflon tube was added the Deoxo-Fluorreagent (13.15 g, 10.9 ml, 59.5 mmol) and BF₃.Et₂O (440 μL). The mixturewas heated at 60° C. for 3 h. On cooling to 0° C., the solution wastreated with MeOH (0.5 ml) and saturated NaHCO₃ (100 ml). After CO₂evolution ceased, the solution was diluted with 20 ml toluene and theorganic layer was separated, dried (MgSO₄), filtered, and evaporated invacuo. The residue was purified by chromatography on silica gel (hexanesas solvent) to obtain the pure product (5.84 g, 85% yield as a 90/10mixture of the title product and the 1,1,2,4-tetrafluoro isomer). MS:m/e 202 (M⁺)

(c) Formation of 1,2-difluoronaphthalene

A solution of the tetrafluoro naphthalene,1,1,2,2-tetrafluoro-1,2-dihydronaphthalene (5.25 g, 25.66 mmol) in THF(15 ml) was treated with 30% aqueous NH₄OH (30 ml) and zinc (8.45 g, 130mmol) (powder) and stirred under N₂ for 4 hours at RT. The reaction wasmonitored by GC/MS for disappearance of the starting material and foundto be complete. The solution was filtered, extracted with hexane (30ml), and filtered through a short silica column (20 g). The hexanesolution was evaporated in vacuo to afford an oil. This crystallized oncooling to room temperature to afford 3.99 g (95% yield) of product. MS:m/e 164 (M⁺)

EXAMPLE 11

Synthesis of 1,2-Difluoronaphthalene from 6-Bromo-2-Hydroxynaphthalene

(a) Formation of 6-bromo-1,1-difluoro-1H-naphthalene-2-one

A suspension of 6-bromo-2-hydroxynaphthalene (5.0 g, 22.42 mmol) in DMF(25 ml) under N₂ was treated with Selectfluor reagent (15.87 g, 44.84mmol) in eight equal portions at 15 min intervals. The mixture wasstirred for a further 1 h, diluted with EtOAc (50 ml), washed with water(2×25 ml), dried (MgSO4), filtered, and evaporated in vacuo.Purification by flash chromatography on silica gel (1:9 ethylacetate/hexanes) furnished the product (5.51 g, 95% yield). MS: m/e 259(M⁺)

(b) Formation of 6-bromo-1,1,2,2-tetrafluoro-1,2-dihydronaphthalene

To a solution of 6-bromo-1,1-difluoro-1H-naphthalene-2-one (5.51 g,21.27 mmol) in toluene (5 ml) under N₂ in a teflon tube was added theDeoxo-Fluor reagent (8.42 g, 7.01 ml, 38.11 mmol) and BF₃.Et₂O (282 μL,2.24 mmol). The mixture was heated at 60° C. for 3 h. On cooling to 0°C., the solution was treated with MeOH (0.5 ml) and saturated NaHCO₃(100 ml). After CO₂ evolution ceased, the solution was diluted with 20ml toluene, and the organic layer was separated, dried (MgSO₄),filtered, and evaporated in vacuo. The residue was purified bychromatography on silica gel (hexanes as solvent) to obtain the pureproduct (4.78 g, 80% yield as a 85/15 mixture of the title product andthe 1,1,2,4-tetrafluoro isomer). MS: m/e 281 (M⁺)

(c) Formation of 1,2-difluoronaphthalene

A solution of the tetrafluoro naphthalene,6-bromo-1,1,2,2-tetrafluoro-1,2-dihydronaphthalene (4.74 g, 16.80 mmol)in THF (15 ml) was treated with 30% aqueous NH₄OH (30 ml) and zinc (8.45g, 130 mmol) and stirred under N₂ for 24 hours at RT. The reaction wasmonitored by GC/MS for disappearance of the starting material and foundto be complete. The solution was filtered, extracted with hexane (30ml), and filtered through a short silica column (20 g). The hexanesolution was evaporated in vacuo to afford an oil. This crystallized oncooling to room temperature to afford 2.62 g (95% yield) of product.

EXAMPLE 12

Synthesis of 9,10-Difluoro Phenanthrene from 9-Phenanthrol

(a) Formation of 10,10-difluoro-10H-phenanthrene-9-one

A suspension of 9-phenanthrol (2.0 g, 10.31 mmol) in DMF (20 ml) underN₂ was treated with Selectfluor reagent (7.30 g, 20.62 mmol) in eightequal portions at 15 min intervals. The mixture was stirred for afurther 1 h, diluted with EtOAc (50 ml), washed with water (2×25 ml),dried (MgSO4), filtered, and evaporated in vacuo. Purification by flashchromatography on silica gel (1:9 ethyl acetate/hexanes) furnished theproduct (2.13 g, 90% yield). MS: m/e 230 (M⁺)

(b) Formation of 9,9,10,10-tetrafluoro-9,10-dihydrophenanthrene

To a solution of 10,10-difluoro-10H-phenanthrene-9-one (2.13 g, 9.28mmol) in toluene (5 ml) under N₂ in a teflon tube was added theDeoxo-Fluor reagent (3.87 g, 3.2 ml, 17.50 mmol) and BF₃.Et₂O (126 μL,1.0 mmol). The mixture was heated at 60° C. for 3 h. On cooling to 0°C., the solution was treated with MeOH (0.5 ml) and saturated NaHCO₃(100 ml). After CO₂ evolution ceased, the solution was diluted with 20ml toluene and the organic layer was separated, dried (MgSO₄), filtered,and evaporated in vacuo. The residue was purified by chromatography onsilica gel (hexanes as solvent) to obtain the pure product (1.96 g 84%yield). MS: m/e 252 (M⁺)

(c) Formation of 9,10-difluorophenanthrene

A solution of the 9,9,10,10-tetrafluoro-9,10-dihydrophenanthrene (1.96g, 7.75 mmol) in THF (15 ml) was treated with 30% aqueous NH₄OH (30 ml)and zinc (2.52 g, 38.75 mmol) and stirred under N₂ for 24 hours at roomtemperature. The reaction was monitored by GC/MS for disappearance ofthe starting material and found to be complete. The solution wasfiltered, extracted with hexane (30 ml), and filtered through a shortsilica column (20 g). The hexane solution was evaporated in vacuo toafford an oil. This crystallized on cooling to room temperature toafford 1.58 g (95% yield) of product.

What is claimed is:
 1. A method for making aromatic compounds having theformula,

where R is a hydrogen atom, a halogen atom, CF₃, a fused aryl, a C₁-C₂₀alkyl, amino, nitro, a C₁-C₁₀ ether or thioether, C₁-C₁₀ ester, aheteroaryl or aryl and said method comprising: (a) mixing adeoxofluorinating agent with a difluoroketone derivative of an aromaticcompound in a solvent to form a tetrafluoro derivative of an aromaticcompound, said difluoroketone compound having one, two or three rings,said rings being separate or fused and said rings optionally containingone or more heteroatoms and one or more substitutions in addition tohydroxy, said difluoroketone derivative having both fluorine atoms on acarbon vicinal to the ketone; (b) mixing the tetrafluoro derivative ofan aromatic compound of (a) in an organic solvent with a reducing agentin aqueous ammonia to form an aromatic compound containing two vicinalfluorine atoms.
 2. The method of claim 1 wherein, said one or moreoptional substitutions on said rings is one or more of a halogen atom, aC1 to C20 alkyl, a C5-C20 cycloalkyl, a C6 to C12 aryl, an amino, anitro, a C1 to C10 alkyl ether or thioether, a C1 to C10 alkyl ester, aCF₃, a R′SO₂O,

where R′ is CF₃, a C1 to C20 alkyl, a substituted or unsubstituted C5 toC10 cycloalkyl, or a substituted or unsubstituted C6 to C12 aryl,wherein the substitution on the cycloalkyl or aryl can be a C1 to C20alkyl or a C5 to C8 cycloalkyl; R″ is a C1-C10 saturated or unsaturatedalkyl; x is an integer from 0 to 10, and y is an integer from 0 to 10.3. The method of claim 1 wherein the solvent in step (a) is toluene, andthe solvent in step (b) is tetrahydrofuran.
 4. The method of claim 1wherein the reducing agent in step (b) is zinc, magnesium, copper, ormixtures thereof.
 5. The method of claim 4 wherein the reducing agent iszinc.
 6. The method of claim 1 wherein the aqueous ammonia in step (c)is buffered with an ammonium salt to maintain a pH of less than
 14. 7.The method of claim 6 wherein the aqueous ammonia is buffered withammonium chloride to maintain a pH of less than
 11. 8. The method ofclaim 1 wherein the difluoroketone is6-(trans-4-propylcyclohexyl)naphthalene-2-one.